Popular Wakefulness Drug May Be Addictive

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Popular Wakefulness Drug May Be Addictive

An alertness drug developed as an addiction-free alternative to amphetamines might be addictive after all.

Researchers have found that people taking modafinil experience a surge of dopamine, an important cognitive neurotransmitter. Such dopamine upswings are seen in people taking Ritalin, and are considered a chemical signature of possible addictiveness.

"It was believed that modafinil won't have a prominent dopaminergic effect and the likelihood of addiction is very low," said study co-author Nora Volkow, director of the National Institute on Drug Abuse. "But the potential for abuse and addiction is likely to be there."

Modafinil was approved by the FDA for treating narcolepsy and sleep disorders in 1998, but has since been used to treat depression, Parkinson's disease and fatigue. It has also become a popular stimulant, used by soldiers to stay awake and by citizens looking for a safe brain boost.

When it was approved, pharmacologists didn't know exactly how it worked, but said that unlike amphetamines and other dangerous stimulants, it didn't boost dopamine levels.

However, subsequent research on animals suggested that modafinil does affect dopamine. That suggestion is affirmed by the latest findings in humans, published Tuesday in the Journal of the American Medical Association. So are the cautions of neuroethicists who worry that the social pressure to take cognition-enhancing drugs could outpace scientific understanding.

An informal survey by the journal Nature found that roughly one in 10 researchers has used modafinil, also marketed as Provigil and Alertec, and non-prescription use is believed to be increasing. Other experimental cognition-enhancing drugs, such as racetams, Adrafinil and donepizil, may soon follow modafinil's medicine-to-enhancement path.

"At the moment we start seeing addictive properties of a substance that was thought to be non-addicting, red flags go up," said Judy Illes, a University of British Columbia neuroethicist. "We're no longer talking about a substance that easily meets safety standards."

Volkow's team gave therapeutic doses of modafinil to 10 men, then injected them with small doses of cocaine labeled with short-lived radioactive isotopes. Using an imaging technology that tracks radioactive particles in the body, they watched the cocaine go to the brain's pleasure centers, where it would normally bind with dopamine receptors.

Instead of binding, the cocaine continued to circulate — evidence, saidVolkow, that modafinil had already swamped the receptors, just as it does in animals. And when dopamine receptors are blocked, circulating levels of dopamine increase.

Volkow cautioned against jumping to conclusions: the findings didn't quantify modafinil's possible addictiveness, and other as-yet-unidentified chemical interactions may counteract the dopamine effects. Medical literature contains isolated reports of abuse, she said, and none of addiction — but that may be because modafinil is relatively new, and researchers haven't looked to see if people were hooked.

In the future, said Volkow, drug-abuse researchers should study modafinil's effects. The FDA could require data of the sort produced by her team, which required a technology not widely used when modafinil was approved.

Even so, it's almost inevitable that the FDA will approve drugs before they're fully understood. "The clinical trial process doesn't produce10 years of data. It's not as exhaustive as we want it to be," saidJosephine Johnston, a bioethicist at the Hastings Center, a nonpartisan think tank.

"Even now, after all the years that it has been on the market, we are still learning things" about modafinil, said University of Pennsylvania neuroethicist Martha Farah. "I think this goes to show that we need a little caution and a little humility when we're messing around with our brain chemistry."*Citation: Effects of Modafinil on Dopamine and Dopamine Transporters in the Male Human Brain." By Nora Volkow, Joanna Fowler, Jean Logan, DavidAxeloff, Wei Zhu, Frank Telang, Gene-Jack Wang, Millard Jayne, JacobHooker, Christopher Wong, Barbara Hubbard, Pauline Carter, DonaldWarner, Payton King, Colleen Shay, Youwen Xu, Lisa Muench, KarenApelskog-Torres. Journal of the American Medical Association, Vol. 301No. 11, March 18, 2009.*

Image: Levels of cocaine binding with dopamine neurotransmitters in the brains of a control group (left) and men taking modafinil (right) / JAMA